Patient cerebral organoids capture Alzheimer's disease proteomic biomarkers and drug targets.

Patient iPSC-derived cerebral organoids are a leading human model of Alzheimer's disease, yet their proteome has never been benchmarked against human disease. Clinical cohorts now nominate thousands of biomarkers and drug targets across three proteomic platforms, and whether patient organoids capture these candidates is unknown. Here, we profile AD and control cerebral organoids containing neurons, astrocytes, and microglia on the three platforms driving clinical discovery, mass spectrometry, SomaScan, and Olink, in both conditioned media and lysate. Benchmarked against 121 studies and clinical cohorts of over 17,000 plasma, CSF, and cortex samples, patient organoids detect almost every nominated candidate and reproduce the disease-associated change in roughly one in four of the most reproducible. This convergence spans plasma, CSF, and cortex, and extends to synaptic, mitochondrial, and proteostatic biology. We provide the first multi-platform reference proteome of a patient-derived AD model, establishing it as a translationally relevant system for studying AD.